This invention relates to a way of determining whether bleeding in the gastrointestinal tract originates in the upper gastrointestinal tract or the lower gastrointestinal tract.
Gastrointestinal bleeding is a common clinical problem with many and varied causes. Gross bleeding into the GI tract is responsible for about two percent of all emergency medical hospitalizations in the United States. Of these approximately 85,000 patients per year, the majority have upper GI bleeding from peptic or gastric ulcers. On the other end of the spectrum are patients with occult GI bleeding. Occult GI bleeding is loss of blood into the digestive tract that is not apparent to the patient or to the physician by physical examination. Studies of healthy subjects between ages 40 and 50 have shown that about 3-6% of individuals have occult blood loss. See Rozen P, Knaani J, Samuel Z, “Comparison of two immunochemical and two guaiac fecal occult blood screening tests for colorectal neoplasia”, Digestive Diseases and Sciences, 1997. 42(10):2064-71. These statistics clearly show the enormous number of patients that have blood loss in the GI tract as an important medical sign.
Whether the bleeding is an acute and significant blood loss or is a slow occult bleed, the first diagnostic question to be considered is the location of the source of bleeding. The clinician attempts to define the bleeding as an “upper GI bleed” or a “lower GI bleed”. This is the key assessment that determines the sequence of patient management. The decision to perform an upper GI endoscopy or lower GI endoscopy, the type of radiographic studies to perform, and the medications that may be prescribed all hinge on the foregoing assessment of the bleeding location.
Many patients that experience a gross, acute bleeding episode are rather easily categorized with respect to the bleeding site according to their clinical history and naso-gastric aspiration (which for example may return blood from the stomach). However, even for acute bleeding, the source of bleeding is not always immediately ascertainable. As many as 10% of duodenal ulcer bleeds have negative naso-gastric aspirations in the emergency room, possibly due to edema or pyloric spasm. Melena in the stool (resulting from bacterial degradation of the blood) can be seen in both upper and lower GI bleeding and may lead to confusion as to the location of the bleeding source. Therefore, even in patients with acute blood loss, a means of distinguishing upper from lower bleeding sites at the point of patient care would represent a useful and needed capability in about 10-15% of the cases.
In contrast, for patients with occult GI bleeding, the source of bleeding is never ascertained by clinical history. The causes of occult GI bleeding are similar to those of clinically apparent bleeding. The majority, about 60-70%, are upper GI bleeds due to peptic/gastric ulcers or erosive gastritis. Gastric ulcers are much more prevalent now than 15 years ago due to the increased use of nonsteroidal anti-inflammatory drugs.
However, the most important application of testing for occult GI bleeding is to detect lower GI bleeding as a screen for colorectal neoplasia. For example, the American Cancer Society recommends that everyone over the age of 50 undergo annual fecal occult blood testing. These screening practices produce a large number of patients with positive occult blood who must then be further evaluated. This generally involves the patient undergoing a colonoscopy exam (with an average cost of about $1,000 per work-up). It has been estimated by the Congressional Budget Office that this screening costs Medicare over $100 million per year. To fully implement this screening for colorectal cancer for all Americans over the age of 50 would cost about $1.2 billion dollars per year. See Ransohoff D F, Lang C A. Screening for colorectal cancer. N. Engl. J. Med.,1991. 325:37. This expensive work-up could be avoided for the majority of patients having an upper GI bleeding source if it were possible to reliably determine that their bleeding is indeed an upper GI bleeding before performing a colonoscopy.
The unavailability of any simple laboratory test to classify GI bleeding as an upper or lower GI bleed is a problem that is well-understood by nearly all clinicians. It is not surprising then that while evaluating a new and highly sensitive fluorometric test (HemoQuant™) for occult blood, the need for such a test prompted Schwartz et al to publish an article suggesting further study of the HemoQuant™ test as a possible means of distinguishing bleeding sites. See Schwartz S, Dahl J, Ellefson M, Ahlquist D., “The HemoQuant test: A specific and quantitative determination of heme (hemoglobin) in feces and other materials”, Clin. Chem. 1985:29:2061-2067. The HemoQuant™ test involves the conversion of heme into dicarboxylic porphyrins (e.g. hematoporphyrin). Heme is a core, non-protein part of hemoglobin that binds iron, and provides much of the material which is visible to spectroscopy. The dicarboxylic porphyrins absorb strongly at 402 nanometers and fluoresce at 653 nanometers. This provides a quantitative and sensitive measure of the hemoglobin present. As discussed above, hemoglobin in the intestines is exposed to a large population of bacteria, which can also degrade hemoglobin to dicarboxylic porphyrins. These products may be measured separately and are called the intestinal converted fraction (ICF). It was postulated that the more proximal the bleeding site the longer the exposure to bacteria and the greater the ICF. Indeed, this was subsequently noted to be the general trend. See Ahlquist D A, McGill D B, Schwartz S, Taylor S F, et al., “Fecal blood levels in health and disease: A study using HemoQuant”, N. Engl. J. Med. 1985. 312:1422-1428. However, after studying a large sample of patients it was found that while the ICF appeared to be affected by the site and amount of bleeding (for example the mean ICF was significantly lower in patients with bleeding from sigmoid or rectal lesions compared to more proximal lesions) it was concluded that the considerable individual differences in enteric heme metabolism severely compromised the predictive value of the ICF. See Goldschmidt M D, Ahlquist D A, Wieand H S, McGill D B, et. al., “Measurement of degraded fecal hemoglobin-heme to estimate gastrointestinal site of occult bleeding: appraisal of its clinical utility”, Digestive Diseases and Sciences, 1988, 33:605-608. Consequently, the ICF was thought to be of no clinical utilitly in estimating the bleeding site.
An alternative approach is described in U.S. Pat. No. 5,064,766, entitled “Method for differentiating the source of occult gastrointestinal bleeding”, issued Nov. 12, 1991 to Wardlaw and Levine. This patent describes the collection of a stool sample on a charged absorbent medium, such as silica, for the purposes of separating hematin and hemoglobin through a process of chromatography. This can be accomplished since the charge on these molecules is different. The location of the hematin and hemoglobin molecules are then visualized by using a guaic color reaction. Thus the relative concentration of the different molecules can be determined. Hematin is a degradation product of hemoglobin that is promoted by exposure to acid in the stomach and the action of bacteria in the lower gastrointestinal tract. The premise is that large amounts of hematin would indicate that the blood originated from the upper gastrointestinal tract. However, bacterial action in the gastrointestinal tract is highly variable with unpredictable amounts of hematin formed, which greatly reduces the specificity of the test. Perhaps for this reason the foregoing method has not seen any practical use.
Therefore, nearly ten years after the development of the closest prior art, there still is no available effective practical test to aid in this critical diagnostic determination.
Thus, there is an unmet need for a technique that economically, rapidly, and reliably indicates whether gastrointestinal bleeding originates in the upper gastrointestinal tract or lower gastrointestinal tract of a patient.